Derivatives of 4b, 5, 9b, 10 tetrahydro-4b, 9b-diphenylindolo-[3, 2-b] indole and process for their preparation



DERIVATIVES F 4b,5,9b,10 TETRAHYDRO-4b,9b- DIPHENYLINDOL0-[3,2-b] INDOLEAND PROC- ESS FOR THEIR PREPARATION Werner Metlesics, Clifton, and LeoHenryk Sternhach, Upper Montclair, N.J., assignors to HoflEmann-La RocheInc.. Nutley, NJ., a corporation of New Jersey No Drawing. Filed May 19,1965, Ser. No. 457,180 5 Claims. (Cl. 260326.9)

The present invention relates to diazocine derivatives. Moreparticularly, it relates to reduction products of diazocines, and toprocesses for their preparation.

5.6-dihydro diazocines of the invention have the formula wherein Rthrough R, are hydrogen, halogen, e.g. F, C1, or Br, lower alkoxy, loweralkylt-hio, or trifluoromethyl,

'and R through R, can be the 'sameor different, except that at least oneof R through R, must be selected from halogen, lower alkoxy, loweralkylt-hio or trifluoromethyl; R through R-; are hydrogen, halogen, e.g.F, C1, or Br, lower alkoxy, lower alkylthio, lower alkyl, ortrifluoromethyl, and R through R7 can be the same or difl'erent; and Ris hydrogen or lower alkyl.

Preferred compounds with the above formula have the formula Bi V N: R Il wherein R is hydrogen or lower alkyl and R and R are hydrogen,halogen, e.g. fluorine, chlorine or bromine, preferably chlorine, ortrifluoromethyl; except, however, at least one but not 'both of R and Ris hydrogen. 1 I

United States Patent 3,282,958 Patented Nov. 1,

"ice

Another group of further reduced diazocines within the scope of theinvention are those having the formula (III) wherein R and R have thesame meaning as given above for the compounds of Formula II and R and Rare hydrogen, lower alkyl, preferably methyl, or, when taken together,form a methylene bridge between the nitrogen atoms.

Another group of compounds within the scope of the invention are thosehaving the formula Rio wherein R and R are hydrogen or lower alkyl and Rand R are hydrogen or halogen, e.g., fluorine, chlorine or bromine,preferably chlorine, or trifluoromethyl, except, however, at least onebut not both of R and R is hydrogen.

The compounds of Formulas I through V exhibit estrogenic activity andare useful as estrogens. Additionally, many of the compounds within theabove genera exhibit antigonadotropic and/or blood pressure loweringactivity and are useful as antigonadotropins and/or hypotensive agents.For example, 3,8-dichloro-. 4b,5,9b,10 tetrahydro 4b,9bdiphenylindo1o[3,2 b] indole; 2,8-dichloro-5,6 dihydro 6,12diphenyldibenzo [b,f] [1,5 ]diazocine; and 2,8 dichloro 5,6 dihydro 5-methyl-6,12-diphenyldibenzo[b,f][1,5]diazocine are very activeantigonadotropins, and 3,8-dichloro-4b,5,9b,10- tetrahydro-5,l0-dimethyl4b,9b diphenylindolo[3,2-b] indole is a very active hypotensive agent.

The term lower alkyl used in the specification and claims is to beunderstood to mean a straight or branched chain alkyl group having from1 to 7 carbon atoms, e.g., methyl, ethyl, propyl, butyl, isopropyl,hexyl, heptyl, etc. and is preferably methyl.

The novel compounds of the invention are prepared by reducing a compoundof the formula R1 Res B R N=l R;

R Q R2 7 R4 Ru Br Br (VI) amino-borane in acetic acid, although insomewhat lower yield. Compounds of Formula I wherein R is lower alkylcan either be prepared (a) from compounds of Formula I wherein R ishydrogen by reaction with a lower alkylating agent, e.g., a lower alkylhalide, a dilower alkyl sulfate, etc. or (b) from alkyl addition saltsof compounds of Formula I, e.g., from the dimethylsulfate salt, byreduction with a Group I metal-Group III metal hydride.

Compounds of Formula D1 can be prepared by reacting a compound ofFormula V1 with hydrogen in the presence of a hydrogenation catalyst,such as platinum, in a hydrogenation solvent such as acetic acid.Alternatively, a Group I metal-Group III metal hydride can be employedusing a liquid aliphatic or cycloaliphatic ether solvent, such astetrahydrofuran, diethyl ether, etc. Alternatively, compounds of FormulaIII can be prepared from compounds of Formula I by employing the abovereducing agents. Where R or R is other than hydrogen, the loweralkylation reaction can be carried out as described above for compoundsof Formula I.

When it is desired to have R and R the same lower alkyl group, thealkylation reaction is carried out on a compound of Formula III whereinR and R are hydrogen. When it is desired to have R a dilferent loweralkyl group than R a compound of Formula I wherein R is one lower alkylgroup is reduced to a compound of Formula III, and a lower alkylationreaction performed thereon using a different alkylating agent. Ofcourse, it is understood that the starting materials of Formula VI orFormula I employed in the reduction will be chosen so as to have theproper groups R and R with no other groups attached to the benzenenuclei. The compounds of Formula IH wherein R and R form a methylenebridge between the nitrogen atoms are prepared by reacting a compound ofFormula III wherein R and R are both hydrogen with formaldehyde.

Compounds of Formula IV are prepared by reacting a compound of Formula Iwith hydrogen in the presence. of a hydrogenation catalyst, such asplatinum, in a hydrogenation solvent such as acetic acid. Alternatively,the reduction can be carried out using nascent hydrogen, e.g. producedby metals such as zinc,.tin, iron, etc. in a basic or an acidic medium,preferably acetic acid.

The starting materials of Formula VI are prepared in accordance with theprocess given in copending applica- -tion Serial'No. 263,411, filedMarch 7, 1963 to Werner Metlesics and Leo Henryk Sternbach, and nowabandoned. The invention will be further understood by reference to thefollowing examples which are given for illustration purposes only andare not meant to limit the invention.

EXAMPLE 1 2,8-dichloro-5,6-dihydro-6,12-diphenyldibenzo [b,f] [1,5]

diazocine To a solution of 86.8 grams (0.203 mole) of 2,8-dichloro-6,12diphenyldizenzo [b,f] [1,5]diazocine in 1000 m1. of pyridine cooled to10 in an ice bath are added 7.6 grams (0.20 mole) of lithium aluminumhydride in small portions with stirring. The cooling isdiscontinuedafter 15-30 minutes and the dark brown solution is stirred at 25 for 16hours. The solution is cooled in an ice bath, 1000 ml. of wet ether and30 grams of ice added in small portions, and the mixture stirred for.1-2 hours at 25. The solution is filtered through Celite and thesolvent removed in vacuo to give yellow needles of 2,8-dichloro- 5,6dihydro 6,12 diphenyldibenzo [b,f] [1,5]diazocine which, afterrecrystallization from a mixture of methylene chloride and ethanol, meltat ZOO-208. (Sometimes remainders are observed up to 230.)

The'above, compound is also obtained by reduction of2,8-dichl0ro-6,12-diphenyldibenzo [b,f], 1,5]diazocine with"dimethylamineborane in acetic acid.

EXAMPLE 2 To a solution of 4.3 grams (0.01 mole) of 2,8-dichloro- 5 ,6dihydro-6,l2-diphenyldibenzo[b,f] [1,5 Jdiazocine in 35 m1. ofdimethylformamide 3.0 grams of a 50 percent suspension of sodium hydridein mineral oil is added and the mixture stirred for 15 minutes. Afteraddition ofS ml. of methyl iodide the stirring is continued for 5minutes. The mixture is poured on ice and extracted with ether. Onconcentrating the ether a small amount of 3,8- dichloro 4b,5,9b,l0tetrahydro-5,10 dimethyl-4b,9b-di phenylindolo[3,2-b]indole (0.2 gram)is isolated and identified in the usual way. The main product,2,8-dichloro-S,6-dihydro-5-methyl 6,12 dipheny-ldibenzo[b,f][1,5]diazocine, melting at 177-l80 is obtained on addition of hexane.

EXAMPLE 3 A solution of 85.8 grams 0.2 mole) of 2,8-dichloro- 5,6dihydro-6,12-diphenyldibenzo[b,f] [1,5]diazoc-ine' in 700 ml. oftetrahydrofuran is added dropwise to a stirred solution of 11.3 grams(0.3 mole) of lithium aluminum hydride in 500 ml. of tetrahydrofuran.Throughout the addition (ca. 45 minutes) the temperature is kept below10 by an ice bath. The mixture is then heated to reflux for 16 hours,cooled and after addition of 600 ml. of wet ether and 25 ml. of Waterstirred for 2 hours. The solution is filtered through Celite and thefilter cake washed with 1000 ml. of tetrahydrofuran. The solvent isremoved in vacuo and the residue repeatedly recrystallized from benzeneto yield cis2,8-dichloro-5,6,11,12-tetrahydro-6,12-diphenyldibenzo[bi][1,5]diazocinein the form of white prisms melting at 225-227".

EXAMPLE 4 Trans 2,8-dichlr0-5,6,11,1Z-tetrahydr0-6,12-diphenyldibenzo[b,f] [1,51diazacine To a stirred solution of 50 grams (0.117 mole) of2,8 dichlor0-6,12-diphenyldibenzo [b,f] [1,5]diazocine in 2500 ml. ofether is added 5.5 grams (0.145 mole) of lithium aluminum hydride. Thesolution is heated to reflux for 16 hours, cooled in an ice bath and 28ml. of 2 N sodium hydroxide is added dropwise. After stirring for 2hours the solids are filtered from the solution. The filter cake isextracted with 1000 ml. of boiling tetrahydrofuran and the suspensionfiltered hot. Ethyl acetate is added to the filtrate and thetetrahydrofuran removed in vacuo. White prisms of trans2,8-dichloro-5,6,l1,12-tetrahydro-6,12 diphenyldibenzo [b,f] [1,5]diazocine are obtained, melting at 244-247". This compound holdssolvents tenaciously and has to be dried in vacuo at 160.

EXAMPLE 5 Cis2,8-dichloro-5,6,11,12-tetrahydr0-5-methyl-6,12-diphenyldibenzo [bj][1,5] diazocz'ne A solution of 8.6 grams (0.019 mole) of 2,8-dichloro-5,6 dihydro 5 methyl-6,l2-diphenyldibenzo[b,f] [1,5] diazocine in 120ml. of tetrahydrofuran containing 1.5 grams (0.04 mole) of lithiumaluminum hydride is heated to reflux for 16 hours. The solution iscooled and 7 ml. of water added. After filtration through Celite a clearsolution is obtained which leaves a crystalline residue on evaporation.Recrystallization from a mixture of benzene and petroleum ether givescis 2,8-dichloro-5,6,11,12-tetrahydro-5-methyl-6,12 diphenyldibenzo[b,f] [1,5]diazocine in the form of white prisms melting at 183-184.

EXAMPLE 6 Trans2,8-dichl0ro-5,6,11,12-tetrahydro-5-methyl-6,IZ-diphenyldibenzo [b,f][1,51diazocine To a solution of 4 grams (0.009 mole) of the cis isomerprepared in Example 5 in 75 ml. of dirnethylformamide prepared undernitrogen is added 4 grams of a 50 percent suspension of sodium hydridein mineral oil. The mixture is stirred at 50 for 2 hours, poured intoice water and extracted with ether. The ether is dried and evaporatedand the residue chromatographed on 150 grams of alumina (Woelrn, No. 1,acidic). With benzene, some cis isomer is obtained. Further elution withethylacetate and methylene chloride gives White prisms of the abovetrans isomer which, after recrystallization from a mixture of benzeneand hexane, melts at 187-189.

EXAMPLE 7 Cis 2,8-dichlor0-5,6,1 I,12-tetrahydr0-5,1I-dim'ethyl-6,12-diphenyl-dibenzo [bj] [1,5] diazocine A solution of 4.3 grams (0.01mole) of cis 2,8-dichloro-5,6,11,12-tetrahydro 6,12 diphenyldibenzo[b,f][1,5] diazocine, prepared in Example 3, in 30 ml. of dimethylformamideis prepared under nitrogen. After addition of 1 gram of a 50 percentsuspension of sodium hydride in mineral oil and 15 minutes stirring 1.5ml. (0.024 mole) of methyl iodide is added and the stirring continuedfor 15 minutes. This procedure is repeated (1 gram of 50 percent sodiumhydride, 15 minutes stirring, 3 ml. of methyl iodide, 30 minutesstirring) and the resulting mixture poured into ice water and extractedwith ether. Evaporation of the ether leaves a crystalline residue which,after recrystallization from a mixture of methylene chloride andethanol, gives cis 2,8-dichloro-5,6,11,12- tetrahydro-5,11-dimethyl 6,12diphenyldibenzo [b,f] [1, 5]diazocine in the form of white prismsmelting at 214- 216.

EXAMPLE 8 Trans 2,8-dichl0r0-5,6,1 1,12-tetrahy dr0-5,1 I-dimetliyl- 6,1Z-diphenyldibenza b, f] [1,5] diazocine A solution of 4.3 grams (0.01mole) of trans 2,8-dichloro-5,6,lLIZ-tetrahydro 6,12diphenyldibenzo[b,f] [1,5]diazocine, prepared in Example 4, is preparedin 50 ml. of dimethylformamide under nitrogen. The solution is cooled to3 and 1.5 grams of a 50 percent suspension of sodiumphydride in mineraloil is added. Stirring is continued for 1 /2 hours at a temperature ofca. 5l0, then 10 ml. of methyl iodide is added slowly and the stirringcontinued for 1 hour at 25 The mixture is poured into ice Water andextracted with ether. Evaporation of the ether leaves a crystallineresidue which is dissolved in benzene, filtered through acidic" aluminaand recrystallized from ether. White prisms of trans 2,8-dichloro5,6,11,12 tetrahydro 5,11 dimethyl 6,12-diphenyldibenzo [b,f],[l,5] diazocine are obtained which melt at 207-209.

EXAMPLE 9 Cz's-exo 2,8-dichl0r0-6,12-diphenyl-6H,12H-5,1I-metlianodibenzo [bj] [1,5] diazocine EXAMPLE 10 Trans2,8-dichl0r0-6,12-diphenyl-6H,12H-5,11-methan0- dibenzo [b,f-] [1,5]diazocine To a solution of 20 grams (0.046 mole) of trans 2,8-dichloro-5,6,1LIZ-tetrahydro 6,12 diphenyldibenzofla, f] [1,5]diazocine,prepared in Example 4, in 600 ml. of toluene 10 grams ofpara-formaldehyde is added and the mixture heated to reflux for 16hours. Para-formaldehyde is filtered from the solution which is removedin vacuo to give white needles which, after recrystallization from amixture of methylene chloride and ethanol, melt at 187192 (sometimesremainders up to 220).

EXAMPLE 11 3,8-dichZora-4b,5,9b,1O-tetrahydr0-4b,9b-diphenylind0l0-[3,2-b1ind0le A solution of 85.4 grams (0.2 mole) of 2,8-dich1oro-6,l2-diphenyldibenzo[b,f][1,5]diazocine in 1000 ml. of acetic acidcontaining ca. 25 grams of hydrogen chloride is hydrogenated at 25 andatmospheric pressure using 2 grams of platinum'oxide as catalyst. Duringthe rapid uptake of hydrogen, a white salt precipitates from thesolution and the consumption stops after the uptake of 5500 ml. ofhydrogen. (0.2 Mole=4800 ml.+500 ml. for the catalyst). The solution isfiltered from the crystalline precipitate and the catalyst, anddiscarded. The solid part is suspended in ice water and made basic withaqueous ammonia. The product is extracted with ether. The ether solutionis washed with water, dried with sodium sulfate and evaporated todryness. The residue is recrystallized from a mixture of methylenechloride and methanol to give 3,8-dichloro-4b,5,9b,l0-tetrahydro-4b,9b-diphenylindolo[3,2-b1indole in the form of white prisms melting at225-228. A sample obtained by chromatography on basic alumina usingbenzene as eluent melts at 228-230.

EXAMPLE 123,8-dichlro-4b,5,9b,10-tetrahydro-5-methyl-4b,9b-diphenylindolo [3,2-b]indole A solution of 86 grams (0.2 mole) of 2,8-dichloro-6,IZ-diphenyldibenzo [b,f] [1,5] diazocine in 450 ml. of henzene and 50ml. (0.54 mole) of dimethyl sulfate is heated to reflux for 16 hours. Oncooling the red solution precipitates yellow crystals which arecollected on a filter and washed with benzene. Recrystallization from amixture of methylene chloride and ether gives tan prisms of 2,8-dichloromethyl 6,12 diphenyldibenzo[b,f]

[l,5]diazociniutm methyl sulfate melting at ca. 150-205 (dec.).

A solution of 81.7 grams (0.148 mole) of the above sulfate salt in 700ml. of acetic acid containing ca. 25 grams of hydrogen chloride ishydrogenated at 25 and 1 atm. using 2 grams of platinum oxide ascatalyst. During the reaction a white salt precipitates from thesolution and the uptake of hydrogen stops at ca. 4900 ml. (expecteduptake ca. 3600 ml. [0.148 mole] plus 500 ml. from catalyst). Theprecipitate is filtered from the solution andwashed with acetic acid.The filter cake is basified with ice and ammonia and the resultingmixture extracted with methylene cholride. The extract after drying oversodium sulfate, concentrating and addition'of ether gives white prismsof 3,8-dichloro-4b,5,9b,10-tetrahydro-S-methyl 4b,9bdiphenylindolo[3,2-b]indole melting at 229-2310.

EXAMPLE 13 3,8 Dichloro 4b,5,9b,l0 tetrahydro-S,l0-dimethyl-4b,9b-diphenyl-indolo[3,2-b]indole To a solution of 8.6 grams of3,8-dichloro-4b,5,9b,l0- tetrahydro-4b,9b-diphenylindolo[3,2-b]indole,prepared in Example 11, in 75 ml. of dimethylformamide prepared undernitrogen is added 6.0- grams of a 50 percent suspension of sodiumhydride in mineral oil. The mixture is stirred and heated to 55 for 30minutes and cooled in a nice bath. After the addition of 10 ml. (0.16mole) of methyl iodide, stirring is continued for 1 hour at 25 and themixture poured into ice water. Extracation with methylene chloride andreplacement of this solvent by ethanol leads to the isolation of3,8-dichloro-4b,5,9b,l0-tetrahydro-5,l0-dimethyl-4b,9b-diphenylindolo[3,2-b]indolein the form of white prisms melting at 253-25 6. Recrystallization froma mixture of benzene and hexane. gives w-hite prisms melting at 261-263.

EXAMPLE 14 3,8 dichloro-4b,5,9b,10-tetrahydrolb,9b-diphenylindolo[3,2-b]-ind0le To a solution of 2 grams of2,8-dichloro-6,IZ-diphenyldibenzo [b,f] [1,5 ]diazocine in a mixture of25 ml. of methylene chloride, 50 ml. of acetic acid in 5 ml. of water isadded 7 grams of zinc dust. The mixture is stirred for 2 hours, pouredinto ice water, made alkaline with sodium hydroxide and extracted withether. Evaporation of the ether gives white prisms of3,8-dichloro-4b,5,9b,10-tetrahydro-4b,9b-diphenylindolo[3,2-b]-indole,which, after recrystallization from methanol, melt at 227-229".

EXAMPLE 15 2,8 dichloro-5,6 dihydro-S-methyl16,IZ-diphenyldibenzo I .f][1,51-diazocine To a stirred, ice cold suspension of 82.3 grams (0.149mole) of 2,8 -dichloro -5-methyl-6, l Z-diphenyldibenzo [b,f][l,5]diazocininum methyl sulfate (prepared in Example 12) is added 8.2grams (0.22 mole) of sodium borohydride. After stirring for one hour at25 C., 750 ml. of water is added slowly and the mixture left at 25 C;for 16 hours. A yellow precipitate forms from which the solvent isdecanted. The precipitate is dissolved in methylene chloride, ethanoladded thereto, followed by concentration of the resulting mixture togive 2,8-dichloro- 5,6-dihydro-5-methyl-6,12-diphenyldibenzo[b,f] 1,5diazocine in the form of pale yellow prisms melting at 181 184 C.

We claim:

wherein R R R and R are selected from the group consisting of hydrogen,halogen, lower alkoxy, lower alkylthio, and trifiuoromethyl, except thatat least one of R R R and R is other than hydrogen; R R and R areselected from the group consisting of hydrogen, halogen, lower alkoxy,lower alkylthio, lower alkyl and trifluoromethyl; and R and R areselected from the group consisting of hydrogen and lower alkyl.

2. A compound of the formula wherein R and R are selected from the groupconsisting of hydrogen, halogen, and trifluoromethyl, wherein at leastone but not both of R and R is hydrogen, and R and R are selected fromthe group consisting of hydrogen and lower alkyl.

3.3,8-dichloro-4b,5,9b,10-tetrahydro-4b,9b-diphenylindolo-[3,2-b]indole.

4. 3,8-dichloro 4b,5,9b,l0 tetrahydro-S,l0-dimethyl-4b,9b-diphenylindolo [3,2b] indole.

5. A process for the preparation of a compound of the formula wherein RR R and R are selected from the group consisting of hydrogen, halogen,lower alkoxy, lower alkylthio and trifluoromethyl, except that at leastone of R R R and R is other than hydrogen; R R and R are selected fromthe group consisting of hydrogen, halogen, lower alkoxy, loweralkylthio, lower alkyl and trifluorornethyl; and R and R are selectedfrom the group consisting of hydrogen and lower alkyl comprisingreacting a compound of the formula R1 (VI) 20 wherein R through R havethe meaning given above with hydrogen in the presence of a hydrogenationcatalyst in acetic acid in the presence of hydrogen chloride.

No references cited.

ALEX MAZEL, Primary Examiner.

MARY U. OBRIEN, Assistant Examiner.

1. A COMPOUND OF THE FORMULA1-R13,2-(2-R5,3-R6,4-R7-PHENYL),3-((2-R1,3-R2,4-R3,5-RPHENYL)-N(-R14)-),3-(2-R5,3-R6,4-R7-PHENYL),4-R4,5-R3,6-R2,7-R1-2,3-DIHYDRO-1H-INDOLE FOG-01 WHEREIN R1, R2, R3 AND R4 ARESELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN, LOWER ALKOXY,LOWER ALKYLTHIO, AND TRIFLUOROMETHYL, EXCEPT THAT AT LEAST ONE OF R1,R2, R3, AND R4 IS OTHER THAN HYDROGEN; R5, R6, AND R7 ARE SELECTED FROMTHE GROUP CONSISTING OF HYDROGEN, HALOGEN, LOWER ALKOXY, LOWER ALKYTHIO,LOWER ALKYL AND TRIFLUOROMETHYL; AND R13 AND R14 ARE SELECTED FROM THEGROUP CONSISTING OF HYDROGEN AND LOWER ALKYL. 3.3,8-DICHLORO-4B,5,9B,10-TETRAHYDRO-4B,9B-DIPHENYLINDOLO-(3,2-B)INDOLE.